Leucovorin is a mixture of diastereoeisomers of the 5-formyl derivative of tetrahydrofolic acid. The biologically active compound of the mixture is the (-)-L-isomer, known as Citrovorum factor or (-)-folinic acid. Leucovorin is a water-soluble vitamin in the folate group and is useful as an antidote to drugs which act as folic acid antagonists. Leucovorin is employed in injection form as leucovorin calcium in an aqueous bacteriostatic preparation containing leucovorin present as the calcium salt pentahydrate of N-[4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteri-dinyl)-methyl -]amino-] benzoyl]-L-glutamic acid. Each 5 mg of leucovorin is equivalent to 5.4 mg of anhydrous leucovorin calcium or 6.35 mg of leucovorin calcium pentahydrate.
The administration of leucovorin calcium, such as by injection, is indicated (a) to diminish the toxicity of and to counteract the effect of inadvertently administered dosages of folic acid antagonists and (b) in the treatment of megaloblastic anemias due to sprue, nutritional deficiency, pregnancy and infancy when oral therapy is not feasible. In the treatment of an accidental overdosage of folic acid antagonist leucovorin should be administered as promptly as possible as the time interval between anti-folate administration, e.g. methotrexate, and leucovorin rescue increases the effectiveness of leucovorin in counteracting hematologic toxocity diminishes. Monitoring of serum methotrexate concentration is essential in determining the optimal dose of duration and treatment with leucovorin so that the resulting levels of tetrahydrofolate are equivalent to or greater than that of methotrexate.
Leucovorin calcium is susceptible to hydrolysis. The rate of degradation due to hydrolysis increases as the pH drops below 7. Because of the desirability of matching the amount of leucovorin administered as an antidote to at least match the folic acid antagonist drugs administered, such as in the treatment of acute leukemia, or to counteract an overdose in the administration of an anti-folate, such as methotrexate, to effect leucovorin rescue and since leucovorin rescue must be administered as promptly as possible, it is desirable to make certain that the leucovorin composition administered is of the desired and/or required strength as indicated on the container of the drug. Since leucovorin undergoes hydrolysis at a pH below 7.0, such as in the range 6.5-7.0, it is therefore desirable to have available and employ a leucovorin composition which is stable and retains its original packaged potency, pH and clarity.
It is an object of this invention to provide a leucovorin composition, such as an aqueous leucovorin calcium aqueous composition, which has improved stability.
It is another object of this invention to provide a method of improving the stability of an aqueous leucovorin composition, such as an aqueous leucovorin calcium composition, wherein leucovorin calcium is dissolved in sterile or bacteriostatic water.
It is yet another object of this invention to provide an aqueous leucovorin composition suitable for injection wherein the leucovorin composition in form for injection use is packaged or treated so as to retain as much as possible and for a relatively long time its original potency, pH and clarity, and having improved stability.
How these and other objects of this invention are achieved will become apparent from the accompanying disclosure. In at least one embodiment of the practices of this invention at least one of the foregoing objects will be achieved.